Project Summary The proposed research encompasses the design of new peptide catalysts to develop methods by which desymmetrization of diarylalkanes may occur. Chiral diarylalkanes are commonly found in drug candidates as potential treatments for cancer, allergies, hypertension, etc. An overarching objective for this proposal is to understand the roles of noncovalent interactions between catalysts and substrates in imparting reactivity and selectivity so that improved catalysts may be designed for a specific outcome. In this context, two desymmetrization methods are planned to explore these fundamental design concepts for peptide catalysts. First, by combining the dynamic kinetic resolution of oxazolones with symmetry- breaking of bis(phenols), access to chiral diarylalkanes with two new stereocenters and the incorporation of amino acid derivatives is possible. Second, an enantioselective C?H amination reaction via desymmetrization of diarylalkanes is proposed through the design of an integrated peptide-metal catalyst. By joining the peptide?s potential for selective molecular recognition with the transformative power of transition metal catalysts, improvements to current C?H functionalization methods, such as low site selectivity, may be achieved. To develop these methods, detailed analysis of the relationship between catalyst structure and function will be executed with the intention of refining new catalyst structures based on this mechanistic insight. The opportunity to gain understanding from unique modes of action could facilitate extension to substrate classes beyond diarylalkanes and alternate C?H functionalization reactions. Synthetically, these new methodologies will provide access to an array of enantioenriched diarylalkanes, which are a common pharmacophore pursued in the medicinal chemistry field. Elucidating specific roles of noncovalent interactions has applications to many areas of chemistry with the potential to transform and improve established methodologies.